Liver cancer is among the most common and malignant human cancers in the world. The incidence of liver cancer is increasing in the United States. The majority of liver cancers are developed over long period of time, often with chronic liver disease. This offers a window of opportunity to eradicate or at least slow the progression of liver cancer. The urgent issue is to identify molecular targets that can be used for early diagnosis and therapeutic intervention. Newly available aptamer and nanoparticle technology provides a unique opportunity for this purpose. In comparison with genomic and proteomic approaches, the aptamer technology can identify markers using intact tumor cells, which will have significant advantages by closely reflecting the physiological state of cancer. The overall objective of our research program is to apply this technology to select and characterize cancer-specific aptamers for human liver cancer early diagnosis and therapy. Our previous work has validated several cancer-specific aptamers, including murine liver cancer. We have established a reliable system to isolate and culture human primary hepatocytes and liver cancer cells. We have also validated an animal model for human liver cancer. In this proposal, we will generate and test human liver cancer-specific aptamers, and validate their application in cancer diagnosis and target therapy. The goal will be achieved through three specific aims: Aim 1: To identify and characterize human liver cancer cell-specific aptamers; Aim 2. To apply aptamers and nanoparticles for human liver cancer diagnosis; Aim 3. To develop novel and effective target cancer therapy using aptamers-nanoparticle-chemotherapy agent complexes. Our investigation will identify aptamers and biomarkers for liver caner in the context of intact cancer cells. The combination of aptamer and nanoparticles will provide a powerful tool for cancer early diagnosis and targeting therapy. The experience we gain will not only be instrumental for subsequent clinical trails but also have significant impact on biomarker discovery of other solid tumors.